The study proposed here seeks to develop efficacious new therapeutic agents for the treatment of cancer. We hypothesize that through the combination of chemistry and an immune effector we can prepare a versatile and effective new class of immunotherapeutics, chemically programmed antibodies or cpAbs. During the first funding period of this grant, we demonstrated that small molecule ligands could be used to effectively program the catalytic antibody 38C2 to target tumors and their supporting vasculature. cpAbs were shown to be effective therapeutics in xenografted human melanoma and breast cancer models as well as syngeneic murine melanoma and colon cancer models. Here we aim to significantly increase the scope of the chemically programmed antibody approach. We will develop versatile and effective linker chemistries that will allow cpAbs to be adapted to work with virtually any combinations of small molecules, peptides, nucleic acids ligands and shRNAs. We hypothesize that the cpAb approach can endow each of these classes of molecules with characteristics that make them more effective cancer therapeutics. We will use these linkers to prepare multifunctional cpAbs that can attack cancers through multiple modes of action such as engaging tumor associated antigens and neutralizing proangiogenic cytokines to selectively kill tumors. We hypothesize that antiangiogenic therapy might be more effective and engender fewer side effects if it can be localized to the tumor site. We further hypothesize that multifunctional cpAbs that simultaneously address tumor associated receptors as well as angiogenic factors will be more potent and broadly applicable therapeutic agents. Given the relevance of our targets in melanoma, breast, colon, ovarian, and head and neck cancers and in angiogenesis in general, successful development of this approach may have many benefits. With multifunctional cpAbs, we will address the therapeutic potential and mechanism of treating cancer in animal models with single cpAbs that target two or more receptors and neutralize proangiogenic cytokines while addressing the question of whether there is a synergistic or additive advantage of combining anti-angiogenic and tumor targeted immunotherapies in cancer. It is anticipated that the results of this work will provide a promising new approach to the treatment of cancer.